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(Circulation. 2006;113:81-89.)
© 2006 American Heart Association, Inc.

Valvular Heart Disease

Deficiency of the 5-Hydroxytryptamine Transporter Gene Leads to Cardiac Fibrosis and Valvulopathy in Mice

A. Mekontso-Dessap, MD; F. Brouri, PhD; O. Pascal, MD; P. Lechat, MD, PhD; N. Hanoun, PhD; L. Lanfumey, PhD; I. Seif, PhD; N. Benhaiem-Sigaux, MD; M. Kirsch, MD, PhD; M. Hamon, PhD; S. Adnot, MD, PhD; S. Eddahibi, PhD

From Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 651 (A.M.-D., O.P., S.A., S.E.), Département de Physiologie, Université Paris XII, CHU Henri Mondor, Assistance Publique–Hôpitaux de Paris, Créteil; Service de Pharmacologie (F.B., P.L.), Hôpital Pitié-Salpêtrière, Paris; UMR 677 INSERM/UPMC (N.H., L.L., M.H.), NeuroPsychoPharmacologie, Faculté de Médecine Pitié-Salpêtrière, Paris; Lab. Neuropharmacologie (I.S.), Faculté de Pharmacie, Université Paris-Sud, Chatenay-Malabry; Service d’Anatomopathologie (N.B.-S.), CHU Henri Mondor, Assistance Publique–Hôpitaux de Paris, Créteil; and Service de Chirurgie Cardiaque (M.K.), CHU Henri Mondor, Assistance Publique–Hôpitaux de Paris, Créteil, France.

Correspondence to S. Eddahibi, INSERM Unité 651 et Département de Physiologie, CHU Henri Mondor, Assistance Publique–Hôpitaux de Paris, 94010 Créteil, France. E-mail eddahibi{at}im3.inserm.fr

Received April 12, 2005; revision received September 12, 2005; accepted September 14, 2005.

Background— Serotonin (5-hydroxytryptamine; 5-HT) overproduction is responsible for cardiac valvular disease in patients with carcinoid tumors. Reduced 5-HT inactivation is one proposed mechanism of the valvulopathy observed in individuals treated with the appetite suppressants fenfluramine and phentermine. One key protein limiting systemic availability of 5-HT is the 5-HT transporter (5-HTT) expressed by platelets and pulmonary vascular cells; 5-HTT is responsible for 5-HT uptake and subsequent inactivation of the amine passing through the lung. Here we investigated whether 5-HTT–deficient (5-HTT-KO) mice developed structural and/or functional cardiac abnormalities and valvulopathy.

Methods and Results— Cardiac endothelial cells expressed large amounts of 5-HTT in wild-type mice. 5-HTT deficiency appeared to be associated with marked interstitial, perivascular, and valvular fibrosis as evidenced by staining of cardiac collagen in 5-HTT-KO mice. Histological analysis provided evidence for valvulopathy characterized by valvular hyperplasia and prominent fibrosis at the attachment site and base of the leaflets. Echocardiography revealed an increase in left ventricular lumen diameter and a decrease in left ventricular diameter fractional shortening. Although 5-HT_1B receptors mediated the 5-HT–induced collagen secretion by human cardiac myofibroblasts, the contribution of this receptor type to valvulopathy was ruled out because double-KO mice deficient in both 5-HTT and 5-HT_1B receptors showed the same cardiac alterations as 5-HTT-KO mice.

Conclusions— The present results establish a link between 5-HTT and the development of cardiac fibrosis and valvulopathy in vivo. 5-HTT-KO mice represent an especially relevant model for studying the mechanisms by which 5-HT induces valvulopathy.

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